Despite being vaccine preventable, rotavirus is the most important cause of severe gastroenteritis among children and kills half a million children each year worldwide. In Zambia, it is responsible for a third of all diarrhea-associated hospitalization and death in children under 5 years. The Centre for Infectious Diseases Research in Zambia (CIDRZ), established a Program for the Awareness and Elimination of Diarrhea (PAED) in 2010 to assist the Ministry of Health in accelerating introduction of rotavirus vaccine and strengthening clinical capacity for diarrheal disease management. Rotarix (GlaxoSmithKline Biologicals), an attenuated human oral vaccine based on the G1P [8] strain, has been selected for introduction in Zambia starting early 2012 through a PAED-supported pilot demonstration program. Although vaccines like Rotarix are a cost effective tool against infectious diseases, and international guidelines recommend their widespread implementation, live oral vaccines can be less immunogenic and efficacious in developing world settings as compared with industrialized countries. Reasons behind this phenomenon are not well understood, but may relate to continued maternal antigen exposure and high level maternal immunity that is passed to the fetus/newborn transplacentally and/or through breast milk. Specific hypotheses include: (i) High-level rotavirus-specific maternal immunity (in the form of anti-rotavirus breast milk IgA and transplacental serum IgG) contributes to failed seroconversion following vaccination. (ii) Malnutrition negatively impacts infant immunity and increases the risk of post-vaccination rotavirus gastroenteritis. (iii) Introduction of rotavirus vaccine will alter te molecular epidemiology of circulating rotavirus strains detected in vaccinated children presenting with severe diarrhea. To address these hypotheses, the proposed study will recruit a prospective cohort of 420 mother-infant pairs. Participants will be enrolled at the time of vaccination and followed for up to four years. Baseline immunological status will be ascertained and seroconversion rates determined a month after full immunization. Incident rotavirus gastroenteritis will be monitored in the vaccinated infants whenever episodes of diarrhea occur; through this surveillance, the sero-strains of rotaviruses causing disease will be tracked over the four year period. Contributions of HIV infection both in mothers and infants, vitamin A and zinc deficiency, weight for age Z-scores as well as mid upper arm circumference will also be assessed. Knowledge gained from this study will inform future interventional trials on strategies to improve rotavirus vaccine effectiveness in the developing world. PUBLIC HEALTH RELEVANCE: Zambia is preparing to introduce routine infant immunization against rotavirus - the most important cause of severe gastroenteritis and diarrhea mortality in children. The goal of this project is to determine the contribution of maternal, viral, and child factors in rotavirus vaccine failure in a prospective cohort of Zambian children. In coordination with a Lusaka Province-wide introduction of rotavirus vaccine, mother-infant pairs will be enrolled at the time of vaccination and followed for up to four years. We will monitor rates of infant rotavirus seroconversion and gastroenteritis in the vaccinated children.